N,N,N&#39;,N&#39;-6-(1-piperazinyl)-2,5-pyridinediamines

ABSTRACT

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R A , R A   1 , R B  R B   1  are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms or R A  and R A   1  or R B  and R B   1  together with the nitrogen atom to which they are attached form a 5- to 6-member heterocycle optionally substituted with alkyl of 1 to 3 carbon atoms and Y is hydrogen or ##STR2## wherein R 6  is selected from the group consisting of hydrogen, --CH 3 , --F and --Cl, R 9  and R 11  form a second bond at 9(11) or R 9  is hydrogen or --F and R 11  is hydrogen, --OH or ═0, R 16  is --CH 3  or hydrogen, R 17  is hydrogen, --OH or acyloxy, the dotted lines indicate the possible presence of a second bond at 1(2) and 6(7)-positions and the wavy line indicates the α- and β-position and their non-toxic, pharmaceutically acceptable acid addition salts having anti-inflammatory and antioxidant activity.

This is a division of Ser. No. 774,568 filed Oct. 9, 1991, now U.S. Pat.No. 5,202, 316 which is a continuation of Ser. No. 497,563 filed Mar.21, 1990, now abandoned.

STATE OF THE ART

Related prior art includes PCT patent applications No. WO.A. 8,701,706and WO.A 8,707,895.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and a novel process and novel intermediates for their preparation.

It is another object of the invention to provide novel anti-inflammatorycompositions and a method of treating inflammation in warm-bloodedanimals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of a compound of the formula ##STR3## wherein R_(A), R_(A) ¹,R_(B) and R_(B) ¹ are individually selected from the group consisting ofhydrogen and alkyl of 1 to 4 carbon atoms or R_(A) and R_(A) ¹ or R_(B)and R_(B) ¹ together with the nitrogen atom to which they are attachedform a 5- to 6-member heterocycle optionally substituted with alkyl of 1to 3 carbon atoms and Y is hydrogen or ##STR4## wherein R₆ is selectedfrom the group consisting of hydrogen, --CH₃, --F and --Cl, R₉ and R₁₁form a second bond at 9(11) or R₉ is hydrogen or --F and R₁₁ ishydrogen, --OH or ═0, R₁₆ is --CH₃ or hydrogen, R₁₇ is hydrogen, --OH oracyloxy, the dotted lines indicate the possible presence of a secondbond at 1(2) and 6(7)-positions and the wavy line indicates the α- andβ-position and their non-toxic, pharmaceutically acceptable acidaddition salts.

Examples of R₁₇ wherein it is acyloxy are acetyloxy, propionyloxy andbenzoyloxy and examples of alkyl for R_(A), R_(A) ¹, R_(B) and R_(B) ¹are methyl, ethyl, n-propyl, isopropyle, n-butyl, tert.-butyl, isobutyl,sec-butyl and preferably methyl or ethyl.

When R_(A) and R_(A) ¹ and/or R_(B) and R_(B) ¹ with the nitrogen atomto which they are attached form a heterocycle, the latter is a saturatedheterocycle, preferably pyrrolidine or piperidine optionally substitutedwith alkyl such as methyl, ethyl, propyl or isopropyl, and morepreferably methyl or ethyl, or an unsaturated heterocycle, preferablypyrrole optionally substituted with alkyl such as methyl.

Examples of suitable acids to form the non-toxic, pharmaceuticallyacceptable acid addition salts are inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,organic acids such as acetic acid, formic acid, propionic acid, maleicacid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalicacid, glyoxylic acid, and aspartic acid, alkanesulfonic acids such asmethane- or ethanesulfonic acid, arylsulfonic acids such as benzene- orp-toluene-sulfonic acids and arylcarboxylic acids such as benzoic acid.

Among the preferred compounds of the invention are those of the formula##STR5## wherein R₆, R₉, R₁₁, R₁₆, R₁₇, R_(A), R_(A) ¹, R_(B) and R_(B)¹, the dotted lines and the wavy line have the above meanings.

Among the preferred compounds of formula I_(B) are those wherein R₆ ishydrogen, those wherein R₉ and R₁₁ form a second bond in the9(11)-position, those wherein R₁₆ is α-methyl, those wherein R₁₇ ishydrogen and those wherein the dotted line in the 1(2)-position is asecond bond and their acid addition salts.

Specific preferred compounds of the invention are N,N,N',N'-tetraethyl-6-(1-piperazinyl)-2,5-pyridinediamine and21-(4-[3,6-bis(diethylamino)-2-pyridyl]-1-piperazinyl)-16α-methyl-.DELTA.¹,4,9(11)-pregnatriene-3,20-dione and their salts.

The novel process of the invention for the preparation of the compoundsof formula I comprises reacting a compound of the formula ##STR6## inwhich R' is an amino protecting group with a product of the formula##STR7## in which Hal is halogen to obtain a product of the formula##STR8## reacting the latter with a product of the formula ##STR9## inwhich R_(1B) and R_(1B) ¹ have the meanings for R_(B) and R_(B) ¹, orare such that one is a monovalent group amino protecting function andthe other is hydrogen, or R_(1B) and R_(1B) ¹ together are a divalentamino protective group to obtain a product of the formula ##STR10##subjecting the latter to a hydrogenation to obtain a product of theformula ##STR11## optionally a) subjecting the latter to the action ofone or two equivalents of a monohalogenated derivative of R_(A) or ofR_(A) ¹ to obtain a product of the formula ##STR12## in which either oneof R_(A1) and R_(A1) ¹, is hydrogen and the other is alkyl, or bothR_(A1) and R_(A1) ¹ are the same alkyl or b) subjecting the compound offormula VII to the action of a monohalogenated derivative of R_(A) or ofR_(A) ¹, and then to the action of a monohalogenated derivative of R_(A)¹ or of R_(A) to obtain a product of the formula ##STR13## in whichR_(A2) and R_(A2) ¹ are different alkyls or c) subjecting the compoundof formula VII to the action of a dihalogenated derivative of butane orpentane optionally substituted with an alkyl of 1 to 3 carbon atoms toobtain a product of the formula ##STR14## in which R_(A3) and R_(A3')form with the atom to which they are attached a 5- or 6-memberedheterocycle, the products of formulae VII, VII', VII" and VII'" beingsubjected to a reaction of unblocking of the group R' and, if desired,of the groups R_(1B) and/or R_(1B) ¹ to obtain a compound of the formula##STR15## in which R_(A), R_(A) ¹, R_(B) and R_(B) ¹ have the abovemeanings, optionally salifying the product of formula I_(A), oroptionally subjecting the same in a neutral solvent and in the presenceof a base to the action of a compound of the formula ##STR16## in whichX is halogen and R₆, R₉, R₁₁, R₁₆, R₁₇, the dotted lines and the wavyline have the same above meanings to obtain a compound of the formula##STR17## and optionally subjecting the latter to the action of an acidto obtain the corresponding salt.

In a preferred embodiment of the process of the invention, the compoundsof formula I_(A) are obtained by reacting a product of formula II inwhich the group protecting the amino function is, for example, acetylwith a product of formula III in which Hal is, for example, chlorine. Inthe product of formula V, the monovalent group protecting the aminofunction of R_(1B) or R_(1B) ^(`) is, for example, benzyl or trityl andwhen R_(1B) and R_(1B) ¹ together are a divalent group, they can, forexample, form together with the nitrogen atom to which they are attached2,5-dimethylpyrrole.

The compounds of formula I_(B) are obtained by reacting a compound offormula VIII in which X is chlorine, bromine or iodine in a neutralsolvent such as dimethylformamide, tetrahydrofuran, methylene chloride,acetonitrile, ethyl ether or acetone in the presence of a base such asan alkali metal carbonate or bicarbonate, preferably sodium or potassiumcarbonate or bicarbonate, triethylamine or diisopropylethylamine withthe N-substituted piperazine of formula I_(A).

In a preferred embodiment of the process of the invention the compoundof formula VIII is 21-iodo-16α-methyl-Δ¹,4,9(11)-pregnatriene-3,20-dione of Pat. Application No. WO 8,701,706 and theneutral solvent is acetone and the base is potassium carbonate.

The compounds of formula I may be obtained in the form of acid additionsalts by known methods which consist in reacting the compound of formulaI with an inorganic or organic acid selected from the list of acidsshown above. Preferred acids of the invention are methanesulfonic acidor fumaric acid.

The anti-inflammatory compositions of the invention are comprised of ananti-inflammatorily effective amount of at least one compound of formulaI and its non-toxic, pharmaceutically acceptable acid addition salts andan inert pharmaceutical carrier. The compositions may be in the form oftablets, dragees, capsules, granules, creams, pomades, suppositories orinjectable solutions or suspensions.

Examples of suitable excipients are talc, starch, aqueous or non-aqueousvehicles, fats of animal or vegetable origin, paraffin derivatives,glycols, the various wetting, dispersant or emulsifying agents andpreservatives.

The compositions may be used in the treatment of inflammatory reactionssuch as the treatment of local inflammatory reactions such as oedema,dermatoses, pruritus, the various forms of eczema and solar erythema, orfor the treatment of acute inflammatory diseases or chronic inflammatorydiseases, for example rheumatoid arthritis, psoriasis or multiplesclerosis.

The compositions of the invention also have an antioxidant activity byinhibition of tissue lipid peroxidation, for example in the kidney andheart and especially in the brain and spinal cord. The compositions alsodisplay a detoxifying activity in acute intoxications associated withthe peroxidation of lipids of brain tissues such as the brain or spinalcord as well as an advantageous anti-inflammatory activity, for examplein the phenomena of acute inflammation mediated by arachidonic acidderivatives.

The compositions may be used in the treatment of biological disordersfollowing trauma. Trauma is understood to mean tissue damage in whichthe generation of lipid peroxides is involved, and which may be producedby a variety of agents, for example physical agents such as contusions,especially cerebral contusions associated or otherwise with localhaemorrhage, or chemical agents such as those used in antitumorchemotherapy, for example adriamycin, or such as those used in cancerimmunotherapy, for example IL-2 or TNF. They are most especiallyadvantageous in the treatment of cerebral ischaemia, especially in thetreatment of cerebral infarction and in the prevention of itsrecurrence, or in the treatment of drug intoxication produced bychemotherapy or immunotherapy or a combination of the two.

The novel method of treating inflammation in warm-blooded animals,including humans, comprises administering to warm-blooded animals ananti-inflammatorily effective amount of at least one compound of formulaI and its salts. The compounds may be administered orally, parenterallysuch as by intramuscular, intra-articular or intrathecal injection, andpreferably by intravenous injection is a bolus or in continuousperfusion, or locally by topical application to the skin or the mucosae.The usual daily dose is 0,01 to 1 mg/kg depending on the conditiontreated, the method of administration and the specific compound. Themore water-soluble salts are preferably used for aqueous formulationsfor intravenous administration.

The compounds of formula VIII used in the process of the invention are21-halo steroids which may be prepared generally, from the corresponding21-hydroxylated steroids by methods known to those skilled in the art,or, for example, according to the process described in patentapplication WO 8,701,706.

21-hydroxylated steroids having a 17α-hydrogen or a hydroxyl are knownsteroids or steroids whose preparation is known to those skilled in theart. They can be prepared from the corresponding 17-keto steroids usingthe processes described in the French patent applications No. 2,462,445and No. 2,498,607. The 17-keto steroids are themselves known productsdescribed in U.S. Pat. Nos. 2,775,602; 2,793,218; 4,189,431; 3,505,365or 2,656,370.

Steroids having an 17α-acyloxy are prepared by acylation of thecorresponding 17α-hydroxylated steroids Steriods having a double bond atposition 9(11) are known products or products prepared by methods knownto those skilled in the art, for example by dehydration of acorresponding 11-hydroxylated steroids with a mixture of methanesulfonylchloride and thionyl chloride.

Steroids having a 1(2) or 6(7) double bond are obtained from thecorresponding Δ⁴ derivative by methods known to those skilled in theart, for example by the action of a p-benzoquinone derivative such aschloranil or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Derivativeshaving a 1(2) double bond may also be obtained biochemically withmicroorganisms such as Arthrobacter simplex.

Steroids having a 6-methyl radical are prepared by methods known tothose skilled in the art, for example by the action of a methylmagnesiumhalide on a corresponding 5(6)-epoxy steroid having a 3-ketone blocked,for example, by an acetal group. Steroids having a 6-fluorine atom areprepared by known methods, for example by addition of the hydrofluoricacid/dimethylformamide complex to a corresponding 5(6)-epoxy steroidhaving a 3-ketone blocked, for example, by an acetal group. Steroidshaving a 6-chlorine atom are prepared by known methods, for example byaddition of the hydrochloric acid/dimethylformamide complex to acorresponding 5(6)-epoxy steroid having a 3-ketone blocked, for example,by an acetal group.

Steroids having a 16 α-methyl are prepared by known methods, for exampleby addition of a methylmagnesium halide in the presence of a copper saltto a corresponding Δ¹⁶ -20 -keto steroid which is itself obtained bydehydration of the corresponding 17-hydroxylated steroid. Steroidshaving a 16 β-methyl radical are prepared by known methods, for examplefrom a corresponding Δ¹⁶ -20-keto steroid which is treated withdiazomethane, heated and then subjected to a hydrogenation reaction.

The compounds of formulae VII, VII', VII" and VII'" are new products andthe subject of the invention. The products of formulae VII, VII', VII"and VII'", as well as all the products of formula I_(A) contrary to whatis stated, cannot be obtained by the preparation described in patentapplication No. WO 8,701,706.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1 N,N,N',N'-tetraethyl-6-(1-piperazinyl)-2,5-pyridinediamineSTEP A: 1-acetyl-4-[6-(diethylamino)-3-nitro-2-pyridyl]-piperazine

A solution of 51.22 g of N-acetylpiperazine in 200 ml of acetonitrilewas added over 50 minutes at 0° C. to a mixture of 78 g of2,6-dichloro-3-nitropyridine, 600 ml of acetonitrile and 66.3 g ofpotassium carbonate and after the mixture was allowed to return to roomtemperature, it was stirred for 75 minutes. The inorganic salts werefiltered off and 180 ml of N,N-diethylamine and 76 g of potassiumcarbonate were added to the filtrate. The mixture was refluxed for 75minutes and after cooling, the inorganic salts were filtered off. Thefiltrate was evaporated to dryness under reduced pressure and the 166.9g residue were crystallized from 200 ml of ethyl acetate to obtain 87.4g of the expected product melting at 120° C.

    ______________________________________                                        IR Spectrum: (CHCl.sub.3)                                                     ______________________________________                                        C = O              1637 cm.sup.-1                                             Conjugated system  1593 cm.sup.-1                                             1st NO.sub.2 band  1569 cm.sup.-1 -1510 cm.sup.-1                             2nd NO.sub.2 band  1346 or 1299                                               ______________________________________                                    

STEP B: N,N,N',N'-tetraethyl-6-(1-piperazinyl)-2,5-pyridinediamine

A mixture of 70 g of the product of Step A, 1500 ml of methanol 61.5 mlof acetaldehyde and 10 g of activated charcoal containing 10% palladiumwas hydrogenated at a maximum pressure of 1250 mbar at 25° C.Approximately 20 liters of hydrogen were absorbed and the catalyst wasfiltered off. The filtrate was evaporated to dryness under reducedpressure and the 89.8 g of residue were taken up in 500 ml of n-propanoland 91.3 g of potassium hydroxide pellets. The mixture was refluxed for3 hours and the cooled solution was poured into 1 liter of ice-coldwater. The product was extracted with methylene chloride and the organicsolution was washed with saturated sodium chloride solution, dried,filtered and concentrated to dryness under reduced pressure. The 58.9 gof residue were chromatographed on silica (eluant: methylenechloride-methanol-ammonia solution (95:5:0.5) to obtain 48.35 g of theexpected product.

Analysis: C₁₇ H₃₁ N₅ ;

Calculated: %C,66.84; %H,10.23; %N,22.93.

Found: C,66.9; H,10.5; N,22.6.

    ______________________________________                                        IR Spectrum: (CHCl.sub.3)                                                     ______________________________________                                        C = C           1596 cm.sup.-1                                                C = N           1560 cm.sup.-1                                                Heteroaromatic  1531 cm.sup.-1                                                                1487 cm.sup.-1                                                ______________________________________                                    

21-(4-[3,6-bis(diethylamino)-2-pyridyl]-1-piperazinyl)16α-methyl-.DELTA.¹,4,9(11)-pregnatriene-3,20-dione

1.395 g of 21-iodo-16α-methyl-Δ¹,4,9(11) -pregnatriene-3,20-dione(prepared by U.S. Pat. No. WO 8.701,706), 40 ml of acetone, 1.88 g ofthe product of Example 1 and 0.9 g of potassium carbonate were mixed atroom temperature and the mixture was stirred for 2 hours 30 minutes andfiltered. The mixture was evaporated to dryness under reduced pressureand the 3.47 g of residue were chromatographed on silica (eluant:cyclohexane-ethyl acetate (7:3) to obtain 1.4 g of the expected productwith a specific rotation of [α]_(D) =±41°±2°5 (c=0.4% in ethanol).

Analysis: C₃₉ H₅₇ N₅ O₂ :

Calculated: %C,74.6; %H,9.15; %N,11.15.

Found: C,74.5; H,9.4; N,11.5.

    ______________________________________                                        IR Spectrum: (CHCl.sub.3)                                                     ______________________________________                                        Δ.sup.1,4 -3-one                                                                          1663 cm.sup.-1                                                                1624 cm.sup.-1                                                                1604 cm.sup.-1                                                                 889 cm.sup.-1                                              Unconjugated ketone                                                                             1714 cm.sup.-1                                                                1701 cm.sup.-1                                              Heteroaromatic    1594 cm.sup.-1                                                                1561 cm.sup.-1                                                                1486 cm.sup.-1                                              ______________________________________                                    

PHARMACOLOGICAL STUDY I) Antioxidant Activity

The antioxidant activity was tested for in vitro by the test offormation of malonyldialdehyde (MDA) which measures lipid peroxidationtriggered: either a) non-enzymatically by ferrous sulfate in 1) brainhomogenates, or 2) rat liver microsomes or b) enzymatically by NADPH andcarbon tetrachloride in rat liver microsomes.

1.1: MDA formation was measured on 10-fold diluted (v/V) homogenates ofbrains of S-D rats (200 g) prepared in Krebs buffer pH 7.4 under theconditions described in J. Biol. Chem. Vol. 262 (1987) P. 10438-10440. 1ml of homogenate was incubated for 60 minutes at 37° C. in the presenceof 25 microliters of ethanol containing or not containing the testproduct, after the addition of 25 microliters of ferrous sulfatesolution prepared immediately before use in water outgassed with argon(200 micromoles final). 0.25 ml of incubated mixture was withdrawn and1.5 ml of 1% strength phosphoric acid, 0.25 ml of a solution containing200 micromoles of deferoxamine (Desferal®, Ciba Geigy) in water, 100microliters of butylated hydroxytoluene (BHT) at a concentration of 8.7mg/ml in ethanol and 0.5 ml of thiobarbituric acid (TBA) at aconcentration of 0.6% in water were added. The mixture was heated to100° C. for 45 minutes and cooled and 4 ml of n-butanol were added. Themixture was centrifuged for 15 minutes at 4000 rpm and the OD of thesupernatant fraction was then read at 535 nm. The reaction blanks in theabsence of FE** were incubated under the same conditions and thepercentage inhibition was calculated as follows: ##EQU1## The resultsare reported in the following Table

    ______________________________________                                        Concentration                                                                             5 × 10.sup.-4 M                                                                    1 × 10.sup.-4 M                                                                    1 × 10.sup.-5 M                       ______________________________________                                        Percentage                                                                    inhibition                                                                    Product of Ex. 1                                                                          74.2 ± 3.8                                                                            67.4 ± 8.6                                                                            60.3 ± 9.1                               Product of Ex. 2                                                                          60.4 ± 4.4                                                                            55.6 ± 1.3                                                                            63.8 ± 4.3                               ______________________________________                                    

1.2: MDA formation was measured on liver microsomes of S-D rats (200 g)prepared from the fraction sedimented at 100,000 g of a liver homogenatein a sucrose buffer, of which the fraction remaining insoluble at100,000 g in 100 mM sodium pyrophosphate buffer pH 7.4 was used andwhich was homogenized in 100 mM sodium phosphate buffer pH 7.4containing 20% of glycerol and was then stored at -80° C.

The microsomes were incubated for 15 minutes at 37° C. in 1 mlcontaining 35 mM Tris-HCl buffet/0.1 M KCl pH 7.4, 1 mg of microsomalprotein, 5 microliters of ethanol containing or not containing the testproduct and 250 microliters of ascorbate solution in the Tris buffer(0.5 mM final), after the addition of ferrous sulfate preparedimmediately before use in the Tris buffer (6 micromoles final). Thereaction was stopped by adding 2 ml of a 1 M solution trichloroaceticacid in 0.25 M hydrochloric acid containing 0.4% of thiobarbituric acid.The mixture was heated to 85° C. for 25 minutes, cooled and centrifugedfor 15 minutes at 3500 rpm. The OD of the supernatant fraction was thenread at 535 nm and the reaction blanks in the absence of Fe⁺⁺ wereperformed at the same time. The percentage inhibition was calculated asabove and the results are as follows:

    ______________________________________                                        Concentration                                                                             1 × 10.sup.-5 M                                                                    5 × 10.sup.-6 M                                                                    1 × 10.sup.-6 M                       ______________________________________                                        Percentage                                                                    inhibition                                                                    Product of Ex. 1                                                                          99.4       99.4       44.0                                        Product of Ex. 2                                                                          99.8       99.5       42.0 ± 5                                 ______________________________________                                    

2: MDA formation was measured on liver microsomes of rats pretreatedwith phenobarbital (80 mg/kg by 3 i.p. injections), prepared asdescribed above. The microsomes were incubated for 15 minutes at 37° C.in 1 ml containing 0.1 M pH 7.4 phosphate buffer, 1 mg of microsomalprotein, 5 microliters of ethanol containing or not containing the testproduct and 5 microliters of carbon tetrachloride (5.5 mM final) afterthe addition of 50 microliters of NADPH solution in the phosphate buffer(1 mM final). The reaction was stopped and the assay was then performedaccording to the conditions described above. The results were asfollows:

    ______________________________________                                        Concentration                                                                             1 × 10.sup.-5 M                                                                    5 × 10.sup.-6 M                                                                    1 × 10.sup.-6 M                       ______________________________________                                        Percentage                                                                    inhibition                                                                    Product of Ex. 1                                                                          96 ± 1  93 ± 0.2                                                                              43 ± 3                                   Product of Ex. 2                                                                          91 ± 1  88 ± 1  49 ± 1.5                                 ______________________________________                                    

II) Anti-Inflammatory Activity

The anti-inflammatory activity was assessed in vivo by measurement ofthe anti-oedematous activity by the test of arachidonic acid-inducedplantar oedema described by Di Martino et al (Agents and Actions, 1987,21 3/4 303). The experimental animals were Sprague-Dawley strain SPFmale rats weighing 150 to 170 g (Iffa Credo).

The test was performed on groups of 8 male rats weighing 130 to 150 g,fasted for 16 hours. Arachidonic acid was injected under the plantaraponevrosis of one hindfoot at a dose of 0.2 mg in a volume of 0.1 ml.The volume of the foot was measured using a water plethysmometer beforeand 1 hour after the injection of arachidonic acid. The differencebetween these two volumes represented the degree of inflammation. Theanimals were treated with the test products or the vehicle alone at thesame time as the injection of arachidonic acid. The test products wereadministered orally in a volume of 4 ml/kg after being suspended in 0.5%strength methyl-cellulose and all the experiments were carried out withdexamethasone administered orally at a dose of 0.5 mg/kg as referenceproduct.

The results were expressed as a change in volume of the foot 1 hourafter the injection of arachidonic acid (AA) in the absence or in thepresence of the test product administered at different doses.Statistical interpretation of the results was performed according toDunnett's test (* p <0.05 - ** p <0.01) or according to the Mann-Whitneytest (° p <0.5 -°° p <0.01). For each dose administered orally, thepercentage of inhibition of the oedema by the test product wascalculated relative to the control.

    ______________________________________                                               Dose   Change in volume of the                                                                         %                                                    mg/kg  foot 1 hour after AA (cm.sup.3)                                                                 inhibition                                    ______________________________________                                        Controls 0        0.58 ± 0.04                                              Product of                                                                             0.5       0.32 ± 0.04** -45                                       Example 2                                                                              1         0.32 ± 0.01** -45                                       Controls 0        0.63 ± 0.01                                              Product of                                                                             20        0.33 ± 0.06** -48                                       Example 1                                                                     ______________________________________                                    

The test products have an anti-inflammatory activity at a low dose,especially the product of Example 2 which displayed high activity at adose of 0.5 mg/kg and above. Under the same experimental conditions,dexamethasone induced a 30 to 40% inhibition of the oedema at a dose of0.5 mg/kg.

Various modifications of the compounds and methods of the invention maybe made without departing from the spirit or scope thereof and it shouldbe understood that the invention is intended to be limited only asdefined in the appended claims.

What is claimed is:
 1. A compound having the formula selected from thegroup consisting of ##STR18## wherein R_(1B) and R'_(1B) areindividually selected from the group consisting of hydrogen and alkyl of1 to 4 carbon atoms or one is hydrogen and the other is a monovalentamino protecting group or together a divalent amino protecting group,R_(A1) and R_(A1') are both alkyl of 1 to 4 carbon atoms or one is alkylof 1 to 4 carbon atoms and the other is hydrogen, R_(A2) and R_(A2') arethe same alkyls of 1 to 4 carbon atoms and R_(A3) and R_(A3') togetherwith nitrogen to which they are attached form a member of the groupconsisting of pyrrolidine, piperidine and pyrrole optionally substitutedwith alkyl of 1 to 3 carbon atoms and R' is hydrogen or an aminoprotecting group.